Immune Checkpoint Therapy in Malaria

Introduction

Malaria, caused by parasitic protozoans of the genus Plasmodium, is a serious, life-threatening disease across most of the developing world. There are 200 million cases of malaria each year and almost 500,000 malaria-related deaths. Over the past decades, more than 100 vaccines have been developed to control malaria and have already been clinically evaluated. However, the vaccine had an efficacy of only 43.6% in the first year of administration, and effectiveness decreased to 16.8% by the fourth year. This result suggests that new strategies that target potential mechanisms of immune evasion by parasites need consideration.

PD-L2 protects against lethal malaria and has translational potential. Fig.1 PD-L2 protects against lethal malaria and has translational potential. (Wykes, 2018)

Malaria and T cell Exhaustion

Parasites in the liver stage are known to be cleared by cytotoxic CD8+ T cells and possibly CD4+ T cells. For blood­stage malaria, antibodies have been shown to play a key role in protection. An increased proportion of CD4+ T cells from individuals with acute-phase infections with Plasmodium vivax (P. vivax), Plasmodium falciparum (P. falciparum), or both had increased expression of CTLA-4, OX40, TNFRSF18, and CD69, suggesting a role for regulatory T (Treg) cells in suppressing immunity to malaria and indicating potential targets of checkpoint control. Besides, expression of the immune checkpoint molecule TIM-3 was significantly increased on key populations of lymphocytes in P. falciparum­infected patients.

Immune Checkpoint Blockade in Malaria

Field studies in malaria-endemic areas have shown increased expression of PD-1 on T cells in malaria-infected individuals compared to control subjects, thus implicating PD-1 in immune evasion. In a study, flow cytometric analysis and automated multivariate clustering have revealed more frequent expression of CTLA-4 or PD-1 on CD4+ T cells from children with complicated malaria compared to uncomplicated malaria.

Recently, a study reported that a multimeric form of PD-L2 fused with the Fc region of immunoglobulin (PD-L2-Fc) given to mice infected with lethal malaria was sufficient to attenuate the lethal infection and mediate survival following reinfections after several months, without additional PD-L2-Fc. Moreover, combined blockade of PD-L1 and LAG-3 with antibodies accelerated the clearance of acute non­lethal blood­stage malaria by improving CD4+ T cell function and increasing antibody titers. In addition, antibody-mediated triggering of OX40 signaling also enhanced CD4+ T helper cell and humoral immunity and thus parasite clearance during non­lethal malarial infections.

Hot Molecules Involved in Malaria
PD-1 PD-L1 CD28 CTLA-4
PD-L2 BTLA GITR TIM-3
CD40 LAG-3 ICOS OX40

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Reference

  1. Wykes, M. N.; Lewin, S. R. Immune checkpoint blockade in infectious diseases. Nature Reviews Immunology. 2018, 18(2): 91.

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